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Carcinoma della Cervice UterinaCronoprogramma
Diagnostico-Terapeutico
Struttura Complessa di Ginecologia OncologicaDirettore: Prof. Stefano Greggi
Pap-test Anormale
Bethesda System, 2001
L-SIL
H-SIL
Pap-test Anormale
ASC-US61%
L-SIL 31%
H-SIL 8% ICC 0%
Pap-test Anormale
Davey, 2004
Solomon (ALTS Group), 2001Stoler, 2001
Sherman, 2001Kristen (ALTS Group), 2006
INCIDENCE: 1.3-5.0%
CYTOLOGIC REVISION
Downgraded to neg 40%
Upgraded to L-SIL 20%
Upgraded to H-SIL 2%
• Low reproducibility level• Low PPV
ASC-US
NEGATIVE 75-85%RISK OF CIN2+ 12%RISK OF CIN3+ 5%
CIN 2-3 Cancer
Microinv. Inv.
ASC-US 5-17
ASC-H 24-94
CIN 3 6-12 1-2
% Upgrading
0.2
ASC-US – HPV-test Triage
SICPCV, 2006
HPV-test
HR + HR -
Colposcopia Pap-test a 12 mesi
+ -
Colposcopia Screening
Statement on HPV DNA test utilization, 2009
HPV-test Triage – Raccomandazioni
p16 Triage (sperimentale)
HPV-test (screening)
HR - HR +
p16-test
+ -
Colposcopia HPV-test a un anno
Carozzi, 2008
ASC-US - ASC-H - L-SIL
SICPCV, 2006
H-SIL – Carcinoma squamocellulare
SICPCV, 2006
AGC
SICPCV, 2006
• Citologia e colposcopia ogni 6 mesi per 2 anni• Controllo annuale per altri 5 anni• Ritorno a screening
Follow-up
SICPCV, 2006
Colposcopia, citologia e HPV-test
Colposcopia e/o citologia +
-
Percorso sec. lesione
Pap-test e HPV-test a 12 mesi
+ -
Colposcopia Screening
Colposcopia e/o citologia -
HPV +
Controllo a 6 mesi
A 6 mesi da trattamento
• Carcinoma squamoso in situ• Carcinoma squamoso inf.
cheratinizzante, non-cheratinizzante, verrucoso
• Adenocarcinoma in situ / tipo endocerv. • Adenocarcinoma endometrioide• Adenocarcinoma a cellule chiare• Ca. adenosquamoso• Ca. adenoide cistico• Ca. a piccole cellule• Ca. indifferenziato• Ca. neuroendocrino
Istotipi
FIGO, 2006
~10%
~80%
I The carcinoma is strictly confined to the cervix (extension to the corpuswould be disregarded)
IA Invasive carcinoma which can be diagnosed only by microscopy, withdeepest invasion ≤5mm and largest extension ≤7mm
IA1 Measured stromal invasion ≤3mm in depth and horizontal extension ≤7mmIA2 Measured stromal invasion >3mm and not >5mm with an extension of not >7mmIB Clinically visible lesions limited to the cervix or pre-clinical cancers > Stage IAIB1 Clinically visible lesion ≤4cm in greatest dimensionIB2 Clinically visible lesion >4cm in greatest dimensionII Cervical carcinoma invades beyond the uterus, but not to the pelvic wall or to
the lower third of the vaginaIIA Without parametrial invasionIIA1 Clinically visible lesion ≤4cm in greatest dimensionIIA2 Clinically visible lesion >4cm in greatest dimensionIIB With obvious parametrial invasionIII The tumor extends to the pelvic wall and/or involves lower third of the
vagina and/or causes hydronephrosis or non-functioning kidneyIIIA Tumor involves lower third of the vagina (No extension to the pelvic wall)IIIB Extension to the pelvic wall and/or hydronephrosis or non-functioning kidneyIV The carcinoma has extended beyond the true pelvis or has involved
(biopsy proven) the mucosa of the bladder or rectum. A bullous edema, assuch, does not permit a case to be allotted to Stage IV
IVA Spread of the growth to adjacent organsIVB Spread to distant organs
Cervical Cancer - FIGO Staging (2009)
Microinvasive CC
• IA
Early CC
• IB1
• IIA1
Locally Advanced CC
(LACC)
• IB2
• IIA2
• IIB
• III
• IVA
Metastatic CC
• IVB
CONIZZAZIONE CERVICALE
EVISCERAZIONE PELVICA
FIGOIA1: stromal invasion ≤ 3 mm in depth, horizontal extension ≤ 7 mmIA2: stromal invasion 3-5 mm in depth, horizontal extension ≤ 7 mm
SGOStromal invasion ≤ 3 mm in depth, no LVSI
Microcarcinoma – Staging Criteria
Microcarcinoma – Treatment
• Total abdominal or vaginal hysterectomy(if VAIN, appropriate cuff of vagina should be removed)
• Observation after cone biopsy (particularly if fertility is desired)
FIGO, 2006
IA1
• Modified RH (Type 2) and pelvic LND• Consider extrafascial H and pelvic LND (if no LVSI)
If fertility is desired:• large cone biopsy + extra-perit. or lpsc pelvic LND• rad. trachelectomy and extra-perit.or lpsc pelvic LND
IA2
Mainly with Pap smears annually after two normal smears at 4 and 10 mos
Follow-up
Cone: Positive margin
In patient with positive margins:
• Vaginal Strict Follow-Up
• Endocervical Repeat Conization oror Stromal Hysterectomy
Microcarcinoma – Cone Positive Margin
Fertility-sparing surgeryCervical Cancer
Radical Trachelectomy
Eligibility criteria
Dargent, 1994
43% of cervical cancer in women <45y (10-15% during childbearing years)
• Vaginal• Abdominal• Laparoscopic• Robotic
• Age < 40-45 years & Strong fertility desire• Diagnosis of invasive cancer (ideally, disease locatedprimarily on the ectocervix)• Exclusion of unfavorable histology• Stage IA1 with LVSI, IA2, IB1<2 cm• No evidence of pelvic N met and/or distant met• Gynecologic oncologist experienced in laparoscopicand radical vaginal surgery
Fertility-sparing surgeryRVT & Cancer prognosis
Overall recurrence and death rates comparable to early-stage cervicalcancer treated by RH or RT
Plant, 2004; Seli, 2005
Review n Recurrence Rates
DeathRates
Darsun, 2007 520 4.2 2.8Sonoda, 2008 548 4.0 2.6Plante, 2008 603 4.5 2.5
Fertility-sparing surgeryRVT & Pregnancy outcome
Pregnancy rate 70%
1st-2nd trimester loss 30%
Review (16 studies: 355 RVT / 161 pregnancies)
Boss, 2005
Pregnancy rate 62%
TAB/EUP 5%1st-2nd trimester loss 27%Deliveries <32 ws 12%
Deliveries >37 ws 65%Currently pregnant 6%
Review (8 studies : 603 RVT / 256 pregnancies)
Plante, 2008
CK Conization
Follow-up
Margins +
Repeat coneLVSI +
Margins -
Pelvic LND
N +RH N - Follow-up
No Res T
Invasive Res T
RH + pelvic LND
Cerv Microca – Conservative Treatment Algorythm
IA2
LVSI -
CERVICAL CARCINOMA
Clinical Assessment
Histotype & Grade
Bladder/Rectum involvement
Parametrial infiltration
FIGO Stage
Vaginal infiltration
Lymphnode mets
T size
• Esame vaginale bimanuale e vagino-rettale (in narcosi)• Colposcopia, biopsia / conizzazione• Currettage endocervicale• Cistoscopia • Retto-sigmoidoscopia• Rx torace (2 proiezioni)• TAC/RMN (PET)
FIGO, 2006
Stadiazione Clinica
CC localmente avanzatoCC apparentemente iniziale
• RX torace
• RMN addome/pelvi
• Visita ginecologica in narcosi• RX torace• RMN addome/pelvi• Uretrocistoscopia• Retto-sigmoidoscopia
Cervical Cancer Comparison of Diagnostic Procedure Utilization
ACRIN 6651/GOG 183 (n=208 ;Stage ≥ IB)
1978 1983 1988-1989 2002
Cystoscopy 64% 80% 52% 8.1%
Sigmoidoscopy 44% 58% 49% 8.6%
Barium enema 58% 60% 32% 0
Intravenous urogram 86% 91% 42% 1.0%
Lymphangiography 18% 11% 14% 0
CT/MRI 16% 54% 70% 100%
Montana, 1995Amendola, 2005
Narayan K, 2003
MRI staging for cervical cancer isnow widely accepted as an optimalmethod for evaluation of tumorvolume, uterine corpus involvement,parametrial invasion, …
Cervical CancerMRI
… but prediction of parametrial,bladder and rectal involvement iscorrect in 75% of cases at best
Bipatt, 2003Narayan, 2005
Follen, 2003
Cervical Cancer Detection of Advanced Stage (>IIB) Cancer
by Retrospective Readers of CT & MRI
ACRIN 6651/GOG 183 (n=208 – Stage ≥ IB)
CT MRI P Value
Mean sensitivity (%) 28 47 0.104
Mean specificity (%) 90 79 0.099
Mean PPV (%) 55 36 0.001
Mean NPV (%) 83 85 0.305
Hricak, 2007
Cervical Cancer Performance of CT & MRI in Detecting
Lymph Node Involvement
ACRIN 6651/GOG 183 (n=208 – Stage ≥ IB)
CT MRI
Sensitivity (%) 31 37
Specificity (%) 86 94
Hricak, 2005
FIGO, 2006
Treatment – Stage IB1, IIA1• Modified RH (Type 2) or RH (Type 3) and pelvic LND• Adjuvant pelvic RT plus BRT• Adjuvant concurrent CTRT (Cisplatin±5FU) ↑ survival in such patients
In younger patients, if post-operative radiation is likely to be given:• ovaries may be preserved and suspended outside the pelvis
• RH tipo III + LA pelvica + sampling N aortici
• RT pelvi + BRT
Se desiderio di prole (solo per IB1):
• trachelectomia radicale + LA pelvica ± sampling N aortici
NCCN, 2009
Treatment – Stage IB1-IIA1
Wertheim (1900)
Okabayashi (1921)
Meigs (1951)
Nerve-sparing (1990s)
Robotics (2000s)
Piver-Rutledge (1974)
Mota-EORTC (2008)
Querleu-Morrow (2008)
Radical Hysterectomy – History & Classification
• Type I (Extrafascial hysterectomy): simple hysterectomy to remove theentire cervical tissue
• Type II (Modified RH): basically, the RH described by Wertheim, toremove more paracervical tissue while still preserving the blood supplyto the distal ureters and bladder
• Type III (RH): first described by Meigs in 1944, with the purpose of awide excision of parametrial and paravaginal tissue
• Type IV (Extended RH): complete removal of the periureteral tissueand a more extensive resection of the paravaginal tissue
• Type V (Partial exenteration): radical removal of disease involving thedistal ureter and/or bladder
Radical Hysterectomy – Piver-Rutledge Classification
Piver, 1974
THE POINT OF TRANSECTION OF THE UTEROSACRAL AND CARDINAL LIGAMENTS IN CLASS II AND III RH
Type 3 RH Type 3 RH Type 2 RH
Radical Hysterectomy – Querleu-Morrow Classification
• Type A (Minimum resection of paracervix): extrafascial hysterectomy,corresponds to the type I RH, with a <10 mm vaginal resection
• Type B (Transection of paracervix at the ureter): corresponds to thetype II RH, with (B2) or without (B1) additional removal of the lateralparacervical lymph nodes, and >10mm vaginal resection
• Type C (Transection of paracervix at junction with internal iliac vascularsystem): corresponds to type III RH, with the ureter completely mobilized,15-20mm of vagina and corresponding paracolpos resected routinely;with (C1) or without (C2) autonomic nerve preservation
• Type D (Laterally extended resection): ultraradical procedures mostlyindicated at the time of pelvic exenteration, with the entire paracervicalresection at the pelvic sidewall including the hypogastric vessels (D1);type D2 includes the resection of adjacent fascial-muscular structures
Querleu, 2008
It is recommended to include the following information in the operativereport:
• All parts defining the type of RH (transection of paracervix andvagina, uterine artery)
• Surgical (fresh sample) and pathological (fixed sample) length ofventral, dorsal and lateral extent of paracervix resection
• Surgical/pathological minimum length of vagina resected
• Minimum distance between tumor and resection margins (whenapplicable)
Quality control and results comparison in RH
The term paracervix replaces others such as cardinal or Mackenrodt’s ligament, or parametrium, and includes that usually named as paracolpium
Querleu, 2008
Type A
Type B1 Type C2
Surgery-related Complications
Rad. Hysterectomy (type III)
+ Pelvic Lymph.
10-15% Severe Perioperative Compl.
20-30% Early/Late Bladder/Rectal Disf.
75% vs 10% (III vs II) Temp. Bladder Disf.
Literature Review
FIGO, 2006
LN Involvement by Stage
FIGO, 2006
Treatment – Stage IB2, IIA2• Primary CTRT• Primary RH and pelvic LND + Adjuvant RT• Neoadjuvant CTRT (3 courses of platinum based CT)+ RH and pelvic LND ± Adjuvant post-operative CT or RT
If positive common iliac or paraaortic nodes:• extended field radiation should be considered
Treatment – Stage ≥ IIB
• Primary CTRT (RT plus BRT)• Primary pelvic exenteration (Stage IVA not involving pelvic sidewall)
If positive common iliac or paraaortic nodes:• extended field radiation should be considered
• Primary CT (Cisplatin)
Unclear impact of CT on palliation and survival
FIGO, 2006
IIB-IVA
IVB
• RH tipo III + LA pelvica + sampling N aortici
• CTRT (RT pelvi + Cisplatino + BRT)
• CTRT (RT pelvi + Cisplatino + BRT) + isterectomia adiuvante
IB2-IIA2
NCCN, 2009
Treatment – Stage IB2-IVA
• CTRT (RT pelvi + Cisplatino + BRT)IIB-IVA
• RT pelvi (volume, invasione stromale, LVSI) ± CT(P)• Follow-up N -
RT pelvi + CT(P) ± BRT (margini vaginali +)N pelvici +Margini +Parametrio +
NCCN, 2009
Terapia Adiuvante & Follow-up
• ogni 3 mesi (1° anno)• ogni 4 mesi (2° anno)• ogni 6 mesi (3-5° anno)• annuali (> 6° anno)
EO gen & gin Pap-test
Rx Torace
Laboratorio
CT/MRI/PET
ogni anno (opzionale)
ogni 6 mesi (opzionali)
su indicazione clinica
(Neo)adjuvant Setting
NACT
SHRINKAGE OF PRIMARY TUMOR
TREATMENT OF LOCO-REGIONAL AND DISTANT MICROMETASTASES
ADDITIONAL LOCAL TREATMENT
BETTER DISEASE CONTROL
SURVIVAL BENEFIT
NACT – Rationale
Italian Multicenter Randomized Study, 2001
NACT + Surgery vs Exclusive RT (LACC)
Stage
IB2-IIB
Stage
III
Endpoint Nr. of events / patient
HR (p value)
SurvivalDFSLoco-regional DFSMetastases-free survival
368/872414/872402/872381/872
0.65 (0.00004)0.68 (0.0001)0.68 (0.0001)0.63 (0.00001)
NACT & Radical Surgery (Locally Advanced Cervical Cancer)
Review & Meta-analysis
The absolute improvement in survival of 15% (8-21%) at 5-years obtained by NACT is of the same magnitude as thatachieved with the standard cisplatin-based CTRT
Cochrane Coll., 2009
EORTC Trial 55994Study Coordinators:
S. GreggiG. Kenter
F. Landoni
IB2; IIA2; IIB
Cervical Cancer (age 18-75)
RANDOM
NACT + Radical Surgery
ExclusiveCTRT
Flow-Chart
IR tipo B o C +LA pelvica o
CTRT
IB1
FU
MRC -Parametri -
N -
RT
MRC + parametri +N +Inf stroma cerv >90%
CT +/- RT
CTNA + IR tipo C +LA pelvica o
CTRT
IB2 - II
CTRT oPelvectomia +LA pelvica
III - IVA
CT sistemica
IVB
RMN addome / pelvi Colposcopia, Rx torace,
SCC Ag, Visita gin. in narcosi,Cistoscopia e Rettoscopia
Stadiazione clinica
Ca invasivo
Ca invasivo
FU
IA1 (margini -)
Vedi algoritmo dedicato
IA2
Ca microinvasivo
Conizzazione Cervicale
Ca microinvasivo Ca non definito / CIN III
Biopsia cervicale
Sospetto K cervice uterina
Carcinoma della Cervice non Radiotrattato1° e 2° anno 3° e 4° anno 5° anno > 5° anno
A 30 gg
Ogni 3 mesi
Ogni 6 mesi
Ogni 6 mesi
Ogni 12 mesi
Ogni 12 mesi
Ogni 12 mesi
Visita ginecologica X X X X X
E.O. generale X X X X X
Colposcopia X X X X
Pap-Test X X X X
Rx torace X X X
RMN addome-pelvi* X X X
Urinocoltura (+ ev. Abg) X X X
CA125 X X X
SCC X X X
Follow-up
Carcinoma della Cervice Radiotrattato1° e 2° anno 3° e 4° anno 5° anno > 5° anno
A 45 gg
Ogni 3
mesi
Ogni 6 mesi
Ogni 6 mesi
Ogni 12 mesi
Ogni 12 mesi
Ogni 12 mesi
Visita ginecologica X X X X X
E.O. generale X X X X X
Colposcopia X X X X X
Pap-Test X X X X
Rx torace X X X
RMN addome-pelvi* X X X X
Urinocoltura (+ ev. Abg) X X X
CA125 X X X
SCC X X X
Rettoscopia X X
*TAC addome/pelvi qualora RMN controindicata
Follow-up